Summary ? Project 3 Mechanisms Underlying Improved Health Span on a Short Term Ketogenic Diet A decrease in mitochondrial mass and function in muscle and neurodegeneration are common complications of aging. Both of these conditions are linked to a decline in physical activity. Even though muscle and brain function are essential to health and quality of life, the molecular chain of events that lead to these devastating conditions and interventions, outside of life long exercise, that slow them remain poorly understood. We have recently shown that a long term ketogenic diet can prevent age-associated loss of muscle and brain function. Since strict diets, like exercise programs, are difficult to maintain throughout life, this study aims to determine whether a short term intervention started late in life is equivalent to the longer term treatment and determine the mechanism underlying the benefits so that novel, less arduous, interventions can be developed to improve the longevity and quality of life in millions of Americans. Specifically, we will look at the role played by acetylation in the effects of a ketogenic diet on mitochondrial mass in muscle and the kynurenine amino transferases (KATs) in the development of neurocognitive decline with age and Alzheimer's disease. Since interventions that improve muscle mitochondrial function improve brain function, the objective of this work is to determine whether a ketogenic diet increases enzymes that prevent a neurotoxin from reaching the brain. Building on previously published research in this area, and strong preliminary data, we have developed the working hypothesis that a ketosis shifts metabolism in a manner similar to exercise resulting in enhanced muscle mitochondrial function and an increase in KATs, enzymes that decrease the amounts of the neurotoxin quinolinic acid in the brain and slow neurodegeneration with age or Alzheimer's disease. We will test this hypothesis by completing these three specific aims: 1) Determine whether ketosis can mimic exercise and reverse the age-related impairments in muscle and brain function; 2) Determine whether an increase in KAT in muscle as a result of ketosis is required and sufficient for the improvement in brain function; and 3) Determine whether increasing acetylation and KAT in muscle can improve learning, memory, and motor function in mice with Alzheimer's disease. This highly innovative proposal explores the molecular mechanism underlying an essential question in aging biology using a completely novel approach where diet is used to prevent hallmarks of aging. The significance of this research is three-fold: 1) It will contribute to a basic understanding of the molecular events leading to age-associated loss of muscle and brain function; 2) It will validate a simple nutritional strategy to improve muscle and brain with aging and thus improve quality of life and reduce mortality in the population; and 3) It will provide a novel molecular target for the development of drugs to slow the progress of Alzheimer's disease. Successful completion of this application is one step towards the long-term objective of our laboratory: to increase quality of life through improved muscle and brain function.